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<p>Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated fatty acids (SFAs) have been linked to lipotoxicity. In this study, patients with secondary lymphedema showed a significantly lower plasma polyunsaturated to saturated fatty acid (PUFA/SFA) ratio compared to BMI-matched controls. Stearic acid, a common dietary SFA, induced apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in human lymphatic endothelial cells. In a mouse model, a short-term high-SFA diet was used to lower the plasma PUFA/SFA ratio, which worsened tail swelling, oxidative stress, ER stress, and tissue damage following lymphatic injury. Switching to a standard chow diet after surgery prevented these effects. Patients with lymphedema&#xa0;also exhibited elevated levels of fatty acid-binding protein 4 (FABP4), a lipid chaperone associated with metabolic stress. FABP4 inhibition reduced stearic acid-induced cell death in vitro and mitigated tissue damage in vivo. These findings suggest a pathogenic role for SFAs and support dietary modulation and FABP4 inhibition as potential therapeutic strategies for lymphedema.</p>

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Saturated fatty acids induce lipotoxicity in lymphatic endothelial cells contributing to secondary lymphedema development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月4日

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  • Karina P Gomes,
  • Jacob Korodimas,
  • Emily Liu,
  • Nirav Patel,
  • Xiaoyan Yang,
  • Susan Goruk,
  • Jaqueline Munhoz,
  • Catherine J Field,
  • Spencer B Gibson

摘要

Lymphedema is a chronic lymphatic disorder characterized by persistent tissue swelling, pain, and recurrent infections, often secondary to cancer treatment, surgery, or obesity. Obesity-associated increases in saturated fatty acids (SFAs) have been linked to lipotoxicity. In this study, patients with secondary lymphedema showed a significantly lower plasma polyunsaturated to saturated fatty acid (PUFA/SFA) ratio compared to BMI-matched controls. Stearic acid, a common dietary SFA, induced apoptosis, oxidative stress, and endoplasmic reticulum (ER) stress in human lymphatic endothelial cells. In a mouse model, a short-term high-SFA diet was used to lower the plasma PUFA/SFA ratio, which worsened tail swelling, oxidative stress, ER stress, and tissue damage following lymphatic injury. Switching to a standard chow diet after surgery prevented these effects. Patients with lymphedema also exhibited elevated levels of fatty acid-binding protein 4 (FABP4), a lipid chaperone associated with metabolic stress. FABP4 inhibition reduced stearic acid-induced cell death in vitro and mitigated tissue damage in vivo. These findings suggest a pathogenic role for SFAs and support dietary modulation and FABP4 inhibition as potential therapeutic strategies for lymphedema.